Alonso-Merino Elvira, Martín Orozco Rosa, Ruíz-Llorente Lidia, Martínez-Iglesias Olaia A, Velasco-Martín Juan Pedro, Montero-Pedrazuela Ana, Fanjul-Rodríguez Luisa, Contreras-Jurado Constanza, Regadera Javier, Aranda Ana
Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 20829 Madrid, Spain;
Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, 20829 Madrid, Spain.
Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):E3451-60. doi: 10.1073/pnas.1506113113. Epub 2016 May 31.
TGF-β, the most potent profibrogenic factor, acts by activating SMAD (mothers against decapentaplegic) transcription factors, which bind to SMAD-binding elements in target genes. Here, we show that the thyroid hormone triiodothyronine (T3), through binding to its nuclear receptors (TRs), is able to antagonize transcriptional activation by TGF-β/SMAD. This antagonism involves reduced phosphorylation of SMADs and a direct interaction of the receptors with SMAD3 and SMAD4 that is independent of T3-mediated transcriptional activity but requires residues in the receptor DNA binding domain. T3 reduces occupancy of SMAD-binding elements in response to TGF-β, reducing histone acetylation and inhibiting transcription. In agreement with this transcriptional cross-talk, T3 is able to antagonize fibrotic processes in vivo. Liver fibrosis induced by carbon tetrachloride is attenuated by thyroid hormone administration to mice, whereas aged TR knockout mice spontaneously accumulate collagen. Furthermore, skin fibrosis induced by bleomycin administration is also reduced by the thyroid hormones. These findings define an important function of the thyroid hormone receptors and suggest TR ligands could have beneficial effects to block the progression of fibrotic diseases.
转化生长因子-β（TGF-β）是最有效的促纤维化因子，其作用机制是激活SMAD（果蝇抗五体不全蛋白）转录因子，这些转录因子与靶基因中的SMAD结合元件相结合。在此，我们表明，甲状腺激素三碘甲状腺原氨酸（T3）通过与其核受体（TRs）结合，能够拮抗TGF-β/SMAD介导的转录激活。这种拮抗作用涉及SMAD蛋白磷酸化减少，以及受体与SMAD3和SMAD4的直接相互作用，这种相互作用独立于T3介导的转录活性，但需要受体DNA结合域中的残基。T3可减少TGF-β诱导的SMAD结合元件的占据，减少组蛋白乙酰化并抑制转录。与这种转录相互作用一致，T3能够在体内拮抗纤维化过程。给小鼠注射甲状腺激素可减轻四氯化碳诱导的肝纤维化，而老年TR基因敲除小鼠会自发地积累胶原蛋白。此外，甲状腺激素也可减少博来霉素诱导的皮肤纤维化。这些发现确定了甲状腺激素受体的一项重要功能，并表明TR配体可能对阻止纤维化疾病的进展具有有益作用。
